Drug and Disease Effects in Parkinson's Psychosis: Revisiting the Role of Dopamine

BACKGROUND: Levodopa and dopamine agonists (dopamine replacement therapy [DRT]) are implicated in Parkinson's disease psychosis (PDP), but the relationship between DRT and neurotransmitter dysfunction inherent to PD remains unclear. OBJECTIVES: To examine the relationship between baseline striatal dopamine transporter (DAT) binding in drug‐naïve idiopathic PD, introduction of DRT, or dose change and incident early‐onset PDP. METHODS: Baseline DAT binding was compared between patients with and without incident psychosis (defined here as hallucinations or delusions), controlling for age, sex, baseline cognition, and prospective DRT in the Parkinson's Progression Markers Initiative cohort. Incident illusions were not considered psychosis symptoms. RESULTS: Of 386 patients, 30 (8%) developed PDP (predominantly hallucinations, mean onset 42 months) and 355 (92%) had either no PDP symptoms (mean follow‐up 64 months) or reported illusions only (111/355, 31%). Incident PDP was associated with reduced baseline striatal DAT binding, controlling for confounders (F (1,377) = 10.9; P = 0.001), but not with a specific DRT regime. A total of 6 patients developed PDP when DRT free. There was no suggestion that PDP onset was coincident with starting levodopa or levodopa dose increase. Incident illusions were not associated with reduced DAT binding. CONCLUSION: The findings highlight the role of disease‐related dopamine mechanisms in the pathophysiology of hallucinations in Parkinson's disease alongside medication. It remains to be determined how dopamine mechanisms, medication, and other neurotransmitter systems implicated in PDP interact.